Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention relates to medicinal preparations for peroral administration containing a cyclosporin, especially cyclosporin A, as pharmaceutically active agent.
• Cyclosporins are cyclic oligopeptides of biological origin, which are used in particular as immunosuppressants.
• the cyclic polypeptide cyclosporin A consists of 11 amino acids.
• cyclosporins possess anti-inflammatory and anti-parasitic activity.
• cyclosporins are therefore not restricted to immunosuppressants, but may be extended to the therapy of various auto-immune diseases and inflammatory conditions, especially also to the treatment of inflammatory disorders in which auto-immune processes play a role.
• auto-immune diseases and inflammatory conditions especially also to the treatment of inflammatory disorders in which auto-immune processes play a role.
• inflammatory disorders include arthritic illnesses, e.g. rheumatoid arthritis or other rheumatic disorders.
• cyclosporins may be used to treat protozoal infections such as malaria.
• cyclosporin-containing medicaments proposed so far are based on the use of an alcohol and/or oils or similar carrier substances in conjunction with one or several surface-active substances. In this way, perorally administrable preparations or also injection preparations are produced.
• a drink solution which has a content of cyclosporin and ethanol, wherein Labrafil M1944CS or M2125 based on polyoxyethylene-7-glycerol-trioleate or is present as surfactant.
• This solution additionally contains corn oil or olive oil.
• the solution is also used to fill gelatin capsules for peroral administration.
• WO-92/09299 relates to perorally administrable liquid medicaments which contain a cyclosporin with a mixture of a hydrophilic solvent and a surface-active substance in the form of polyoxyethylene-polyoxypropylene block polymers (poloxamers, with a molecular weight of 1000 to 15,500).
• a disadvantage of these formulations is the precipitation of the active ingredient upon contact with aqueous solutions.
• a cyclosporin capsule preparation which contains as carriers and excipients, apart from ethanol and propylene glycol, various corn oil glycerides, glycerin and macrogol-glycerol-hydroxy-stearate, as well as ⁇ -tocopherol.
• cyclosporin-containing preparations are known for intravenous administration, with one or several polyethylene glycol derivatives having the hydroxy-fatty acid moiety bonded in the molecule, together with one or several alcohols as cosolvent.
• the preferred surfactant in the form of the polyethylene glycol derivative is polyethylene glycol-660-12-hydroxy-stearate.
• a series of other polyethylene glycol derivatives are also disclosed, e.g. polyethylene glycol-9-hydroxy-myristate or polyethylene-glycol-9-hydroxy-palmitate.
• the preparations having this composition represent injection concentrates, as disclosed in detail in particular in example 1.
• These concentrates indicated as drug preparations contain for example 4.85% by weight of cyclosporin A, which when used for intravenous application, has to be diluted prior to the injection with an isotonic solution of saline, glucose, dextran, fructose or mannitol.
• cyclosporin A which when used for intravenous application, has to be diluted prior to the injection with an isotonic solution of saline, glucose, dextran, fructose or mannitol.
• saline glucose, dextran, fructose or mannitol
• the preparations described are concerned exclusively with intravenously administrable formulations.
• the disadvantage of these preparations is that they have to be administered in clinics by trained personnel.
• cyclosporins for use in the compositions of this invention are cyclosporin A and ([3'-desoxy-3-oxo-MeBmt] 1 -[Val] 2 -Ciclosporin), the latter disclosed and claimed in EP 296 122.
• the problem according to the invention comprises formulating pharmaceutical compositions, e.g. cyclosporin preparations, which may be administered perorally, have satisfactory bioavailability, low inter-subject and/or intra-subject variability and stability, e.g. in softgels, and in particular can be taken orally by the patient himself.
• pharmaceutical compositions e.g. cyclosporin preparations, which may be administered perorally, have satisfactory bioavailability, low inter-subject and/or intra-subject variability and stability, e.g. in softgels, and in particular can be taken orally by the patient himself.
• a solution to this problem surprisingly consists in processing a cyclosporin into drug preparations to be administered perorally together with one or more polyethylene glycol derivatives with the hydroxy-fatty acid moiety bonded in the molecule and one or more alcohols as solvent, optionally additionally using fatty acid mono-, di- or triesters and/or the glyceride of ricinoleic acid together with linoleic, palmitic and stearic acid glycerides, as well as ethanol and/or propylene glycols (1,2-propylene glycol as cosolvents or surfactants or carriers).
• this invention provides a pharmaceutical composition for peroral administration comprising
• this invention provides a composition containing additionally (d) a C 2 -C 3 -alcohol having one or two hydroxy groups.
• this invention provides a composition containing additionally (d) ricinoleic acid glyceride(s) together with smaller proportions of multiply unsaturated fatty acid glycerides or castor oil.
• Component b) may be present as sole surfactant.
• composition may consist solely of active ingredient (a), and components (b), (c) and (d).
• Components (a), (b) and (d) may be present in a weight ratio of 1 to 4 parts by weight (a) : 6 to 15 parts by weight (b) : 3 to 12 parts by weight (c).
• the bioavailability which may thus be attained is comparable both in respect of the intravenously administrable concentrates, which, upon application, are diluted in a weight ratio of 1:20 to 1:100 with water or with the corresponding solution allowing an isotonic state, and in respect of the commercial preparation of the prior art in the form of solutions or capsule preparations.
• the active agent e.g. the cyclosporin
• the active agent is present in an amount of between about 1 to about 20 wt-%, preferably about 3 to about 15 weight-% based on the weight of the composition.
• Polyethoxylated saturated hydroxy fatty acids may be produced by reacting a saturated hydroxy fatty acid with e.g. ethylene oxide or polyethylene glycol.
• Preferred molecular weights of the polyethoxylated moiety are from 250 to 800 daltons, e.g. 500 to 700.
• the fatty acid may be e.g. of 16 to 18 carbon atoms, e.g. C18, e.g. derived from castor oil.
• the hydroxy group is conveniently attached to a carbon atom located, e.g. from 4 to 8 carbon atoms from a distal methyl group.
• the polyethoxylated saturated hydroxy fatty acid may be obtained in conventional manner, e.g. using an appropriate condensation catalyst.
• the polyethoxylated saturated hydroxy fatty acid may be obtainable by reacting a saturated hydroxy fatty acid with ethylene oxide or with polyethylene glycol.
• the reaction mixture may contain a mixture of components, e.g. unreacted polyethylene glycol and polyethylene glycol ethers of the hydroxy group.
• Saturated hydroxy-fatty acid polyethylene glycol esters suitable for the compositions of this invention are known and commercially available, e.g. from the BASF company under the trade mark Solutol.
• the saturated hydroxy-fatty acid polyethylene glycol ester component may be present in an amount of between about 15 and 95 weight-%, preferably between 20 and 80 weight-%, and more preferably between about 50 and 75 wt-% based on the weight of the composition.
• Solutol® HS 15 which is known, e.g. from BASF technical leaflet MEF 151e (1986), to consist of about 70% polyethoxylated 12-hydroxystearate by weight and about 30% by weight unesterified polyethylene glycol component.
• Solutol® HS 15 has a hydrogenation value of 90 to 110, a saponification value 53 to 63, acid value maximum 1, and a maximum water content of 0.5% by weight.
• Solutols, e.g. Solutol HS 15 have been used in injectable compositions.
• the alcohol may be a C 2 -C 3 -alcohol having one hydroxy group, e.g. ethanol, or two hydroxy groups, e.g. a diol. If present, the alcohol may be in an amount of up to about 40 wt-%, e.g. 5 to 30 wt-% based on the weight of the composition.
• the alcohol may be substantially anhydrous, e.g. 96% ethanol.
• the diol may be propylene glycol.
• a mixture of ethanol and propylene glycol may be present, e.g. in a weight ratio of ethanol to propylene glycol from 2:1 to 1:2, e.g. 1.852 to 1.
• the fatty acid mono-, di- and/or triesters may comprise mono-, di- and/or tri-glyceride mixtures, e.g. of linoleic, palmitic and stearic acids, e.g commercially available under the trade mark Cutina, e.g. Cutina MD described in H.P. Fiedler, Lexikon der Hilfstoffe p.334-335 (1989). If present, the fatty acid mono-, di- and triesters may be in an amount of up to about 60 weight-%, e.g. 20 to about 50 wt-% based on the weight of the composition.
• Castor oil may be present in an amount of up to about 30 wt-%, e.g. 10 to 20 wt-%, based on the weight of the composition.
• a soft gelatin capsule preparation with 5.0 parts by weight cyclosporin A, 65.0 parts by weight polyethylene glycol-660-12-hydroxy-stearate (Solutol HS 15 from BASF company) and 28.0 parts by weight 96% ethanol.
• Soft gelatin capsules containing compositions of the present invention may be prepared as described for example in published European patent application EP 649 651 the contents of which are incorporated herein by reference.
• [3'-desoxy-3'-oxo-MeBmt] 1 -[Val] 2 -Ciclosporin has been found to be effective in reversing multiple drug resistance syndrome.
• [3'-desoxy-3'-oxo-MeBmt] 1 -[Val] 2 -Ciclosporin and its utility is described in detail in EP 296 122.
• compositions of this invention are useful for the known indications of the cyclosporin, e.g. for the following conditions:
• each unit dosage will suitably contain between 1mg and 100 mg of the drug substance, more preferably between 10 and 50 mg; for example 15, 20, 25, or 50 mg.
• Such unit dosage forms are suitable for administration 1 to 5 times daily depending upon the particular purpose of therapy, the phase of therapy and the like.
• compositions to be administered depends on several factors, for example the desired duration of treatment and the rate of release of the active ingredient.
• compositions can be observed in standard clinical tests in, for example, known indications of active agent dosages giving equivalent blood levels of active agent; for example using dosages in the range of 1 mg to 1000 mg, e.g. 5mg to 100mg, of active agent per day for a 75 kilogram adult and in standard animal models.
• dosages in the range of 1 mg to 1000 mg, e.g. 5mg to 100mg, of active agent per day for a 75 kilogram adult and in standard animal models The increased bioavailability of the drug substance provided by the compositions can be observed in standard animal tests and in clinical trials.
• an indicated adult daily dose following renal transplantation is from 50 to 200 mg/day.
• excipients may be present, e.g. microcrystalline cellulose, or SiO 2 , e.g. Aerosil (H.P. Fiedler) in an amount of up to about 5% by weight, e.g. 1 to 4 wt-%, based on the total weight of the composition.
• microcrystalline cellulose or SiO 2
• Aerosil H.P. Fiedler
• the dosage form used may be coated, for example using an enteric coating.
• Suitable coatings may comprise cellulose acetate phthalate; hydroxypropylmethylcellulose phthalate; a polymethyacrylic acid copolymer, e.g. Eudragit L, S; or hydroxypropylmethylcellulose succinate.
• compositions of Examples 1 to 4 are prepared whereby the ethanol component (ethanol and/or propylene glycol) is mixed with the Solutol HS 15 and the active ingredient is dissolved therein whilst stirring.
• a fatty acid mono-, di- and triester, a glyceride of ricinoleic acid and/or a thickener is optionally added to the solution.
• compositions obtained are subsequently filled for example in liquid form into hard or soft gelatin capsules of the desired size, in the desired concentration.
• the compositions may also be further processed in known manner into tablets.
• the active ingredient is dissolved in a mixture of Solutol HS 15 and castor oil.
• the solution thus produced is added whilst stirring to the molten component Cutina MD.
• the liquid melt is poured out, and after solidifying is pulverized in a sifting machine.
• the granulates obtained are mixed with conventional excipients such as lubricants and liniments, disintegrants, fillers, flavourings etc., and the mixtures pressed into tablets with the desired content of cyclosporin; an example of a conventional excipient is silicon dioxide available commercially under the trade mark Aerosil (Degussa, Germany).
• the tablets may be coated with specifically desired coatings to improve taste, for aesthetic reasons or to control release of the active ingredient in the intestines, e.g. to control gastric juice resistance or solubility in the small intestine.
• liquid melts may be directly filled into blisters.
• a group of beagles was used for the experiments and to compare the bioavailability values of the capsule preparations according to the invention.
• the test preparations were applied perorally to fasted animals using stomach tubes.
• Blood was taken from the vena saphena of the animals at pre-determined time intervals, and collected in appropriate plastic tubes with an addition of EDTA.
• the blood samples were stored at -18°C until used for evaluations.
• the cyclosporin evaluation was made in whole blood by means of fluorescence polarisation immunoassay (FPIA).
• AUC areas under the curves
• the average AUC values of the compositions according to the invention are illustrated in the following table, in a comparison with the commercial preparation of cyclosporin capsules (Sandimmun® Optoral), which were determined in the same reproducible way, at the same dosage, using the same dogs.
• composition according to the invention the applicants have succeeded in making available a compact dosage form, for example tablets, with a cyclosporin content, i.e. a medicinal form, which is easy to produce, to handle and to administer, and in addition is economical to produce.
• Encapsulation of the formulations into soft gelatin or hard gelatin capsule preparations is effected in conventional manner or by using the process for soft gelatin capsules as described in EP 649651.
• the preparations according to the invention did not show any precipitation, decomposition or other changes even after storage for 6 months.
• cyclosporins including the analogues and derivatives thereof, are suitable for use in the preparations according to the invention. Examples of such cyclosporins may be found for example in DE-OS 40 03 844 and DE-OS 40 05 190. Cyclosporin A is preferred.
• compositions containing ([3'-desoxy-3'-oxo-MeBmt] 1 -[Val] 2 -Ciclosporin) instead of Cyclosporin A may be prepared in analogous manner to the compositions described in Examples 1 to 4 above.
• the concentration of active ingredient in the oral form of administration according to the invention is 20 to 200 mg, preferably 50 to 100 mg per unit dose. References to weight of composition as used herein ignore the weight of any encapsulating medium, e.g. softgel capsule shell.

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• Health & Medical Sciences (AREA)
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• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
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• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
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• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Gastroenterology & Hepatology (AREA)
• Tropical Medicine & Parasitology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Rheumatology (AREA)
• Transplantation (AREA)
• Pain & Pain Management (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1995
  • 1995-11-29 DE DE19544507A patent/DE19544507B4/de not_active Expired - Fee Related
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• 1996
  • 1996-11-27 PE PE1996000846A patent/PE22598A1/es not_active Application Discontinuation
  • 1996-11-27 IT IT96RM000810A patent/IT1288395B1/it active IP Right Grant
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• 1998
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• 2000
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• 2002
  • 2002-04-03 JP JP2002100996A patent/JP3831676B2/ja not_active Expired - Lifetime

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